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Post-Menopausal Women Have increased HIV transmission risk and
Higher TDF Blood Levels
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Healthy Post-menopausal Women Have Higher Percentages of CCR5+ Cervical CD4+ T Cells Compared to Pre-menopausal Women: Implications for HIV Transmission
Reported by Jules Levin
CROI 2011 March 2 Boston
"Elevated percentages of R5+CD4+ T lymphocytes in cervix may increase the risk for HIV acquisition in post-menopausal vs pre-menopausal women. The correlation between age and cervical expression of R5, suggests elevated R5 expression on cervical CD4+ T cells may be related to aging. Nonetheless, further research is needed to determine if these changes are primarily due to aging or changes in female sex hormones that occur at menopause."
Amie Meditz*1, K Moreau1, W Gozansky1, K Melander1, W Kohrt1, M Wierman1,2, and E Connick1
1Univ of Colorado Denver, Aurora, US and 2Denver VAMC, CO, US
Background: New HIV infections are increasing in US women over age 50 largely through heterosexual transmission. Little is known about the specific effects of aging on immunologic mechanisms that may put mature women at increased risk for HIV. Elevated expression of CCR5 (R5), and the activation markers HLA-DR (DR) and CD38 (38) on CD4+ T lymphocytes has been linked to HIV susceptibility. We hypothesized that these measures would be higher in cervical CD4+ T cells of healthy post-menopausal compared to pre-menopausal women.
Methods: Whole blood was collected from healthy pre-menopausal (early follicular phase, day 1 to 5 of menstrual cycle) and post-menopausal women. None were receiving hormonal therapy. Simultaneous cervical brush samples were collected in a subset of subjects. Samples were stained on the day of collection with monoclonal antibodies and analyzed by flow cytometry. Numbers of R5 molecules on CD4+ T cells (mol/cell) were determined using QuantiBRITEa beads. Data were analyzed by nonparametric statistics.
Results: Median ages of post-menopausal (n = 24) and pre-menopausal women (n = 21) were 55 (range 50 to 65) and 34 (range 23 to 49) years, respectively. Percentages of DR+38+CD4+ T cells were higher in the cervix (8.5%) than in paired whole blood samples (1.3%, p <0.001, n = 17). Percentage of cervical CD4+ T cells co-expressing DR and 38 did not correlate with age (p = 0.2). Post-menopausal women had higher percentages of R5+CD4+ and R5+DR+38+CD4+ T cells than pre-menopausal women in both cervix and whole blood (see the table). The number of R5 molecules per cell did not differ, with the exception that there were more R5 molecules on DR+38+CD4+ T cells in the cervix of post-menopausal vs pre-menopausal women (see the table). Age directly correlated with percentage of R5+CD4+ T cells and R5+DR+38+CD4+ T cells in cervix (r = 0.58, p = 0.004 and r = 0.60, p = 0.01) and in whole blood (r = 0.47, p <0.001 and r = 0.48, p <0.001).
Conclusions: Elevated percentages of R5+CD4+ T lymphocytes in cervix may increase the risk for HIV acquisition in post-menopausal vs pre-menopausal women. The correlation between age and cervical expression of R5, suggests elevated R5 expression on cervical CD4+ T cells may be related to aging. Nonetheless, further research is needed to determine if these changes are primarily due to aging or changes in female sex hormones that occur at menopause.
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Pharmacokinetics of TDF in Blood Plasma and Cervicovaginal Fluid of HIV+ Post-menopausal Compared with Pre-menopausal Women
"The blood plasma and genital tract AUC and trough concentrations of TDF, are significantly increased in post-menopausal women receiving chronic TDF. This suggests that aging and the associated physiological changes affect systemic drug disposition, but also drug penetration into sanctuary sites. Further investigation into the cause of these alterations is warranted."
Kristine Patterson*, J Dumond, H Prince, E Kraft, J Eron, and A Kashuba
Univ of North Carolina at Chapel Hill, US
Background: Menopause results in many physiologic changes, including vaginal thinning and diminished genital tract secretions. Understanding how these changes impact systemic and genital tract ARV exposure in post-menopausal women compared to pre-menopausal women is critical as the HIV+ population ages.
Methods: First dose and steady state pharmacokinetics were performed in 6 HIV+ post-menopausal women initiating a new ARV regimen that included 300 mg tenofovir disoproxil fumarate (TDF) and results compared with 12 pre-menopausal women who underwent identical evaluations; 8 paired blood plasma and direct cervicovaginal fluid aspirates were collected over 48 hours on days 1 to 2 (first dose) and days 28 to 29 (steady state). Tenofovir was measured by validated by LC/MS/MS (LLOQ = 0.1 ng/mL). Data were analyzed by noncompartmental methods using WinNonlin Pro 5.2. Nonparametric statistics were performed using SAS JMP 7. Median (IQR) data are reported.
Results: Pre- and post-menopausal women had a median age of 35 (31 to 42) and 57 (52 to 68); body mass index 25 (24 to 28) and 27 (23 to 29), CrCl 86 (58 to 112) and 76 (65 to 104) mL/min, respectively. We enrolled 10 African American and 2 white pre-menopausal women; and 5 African American and 1 Hispanic post-menopausal women. After first dose, blood plasma exposure was similar, but genital tract exposure was increased in post-menopausal women resulting in an increased genital tract : blood plasma ratio. At steady state, post-menopausal women had greater exposure in both blood plasma (p = 0.02) and genital tract (p = 0.01), resulting in similar genital tract : blood plasma ratios. C24h was greater in blood plasma (p = 0.04) and genital tract (p = 0.01) in post-menopausal women at steady state. In post-menopausal women, blood plasma AUC and blood plasma C24h exceed standard pharmacokinetic parameters by 160% and 125%, respectively.
Conclusions: The blood plasma and genital tract AUC and trough concentrations of TDF, are significantly increased in post-menopausal women receiving chronic TDF. This suggests that aging and the associated physiological changes affect systemic drug disposition, but also drug penetration into sanctuary sites. Further investigation into the cause of these alterations is warranted.
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